Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate
Year: 2021
Type: preprint
Study design: Observational Study
Abstract: The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact DNMs that contribute to the risk of nsCL/P, we conducted whole genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs that contribute to the risk of nsCL/P. These include novel loss-of-function DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.
Source: Research Square
Authors: Waheed Awotoye, Peter A. Mossey, Jacqueline B. Hetmanski, Lord Jephthah Joojo Gowans, Mekonen A. Eshete, Wasiu L. Adeyemo, Azeez Alade, Erliang Zeng, Olawale Adamson, Thirona Naicker, Deepti Anand, Chinyere Adeleke, Tamara Busch, Mary Li, Aline Petrin, Babatunde S. Aregbesola, Ramat O. Braimah, Fadekemi O. Oginni, Ayodeji O. Oladele, Abimbola Oladayo, Sami Kayali, Joy Olotu, Mohaned Hassan, John Pape, Peter Donkor, Fareed K.N. Arthur, Solomon Obiri-Yeboah, Daniel K. Sabbah, Pius Agbenorku, Gyikua Plange-Rhule, Alexander Acheampong Oti, Rose A. Gogal, Terri H. Beaty, Margaret Taub, Mary L. Marazita, Michael J. Schnieders, Salil A. Lachke, Adebowale A. Adeyemo, Jeffrey C. Murray, Azeez Butali
Institutions: University of Iowa, University of Dundee, Johns Hopkins University, Kwame Nkrumah University of Science and Technology, Addis Ababa University, University of Lagos, National Human Genome Research Institute, University of KwaZulu-Natal, University of Delaware, Obafemi Awolowo University, University of Port Harcourt, University of Pittsburgh
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4200411712